Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. ALK fusion genes have been identified in anaplastic large cell lymphomas (ALCL; Morris, S. W. eta al., Science 263: 1281 (1994)), inflammatory myofibroblastic tumor (IMT; Griffin, C. A. et al., Cancer Res. 59: 2776 (1999)), squamous cell carcinoma (SCC; Jazii, F. R. et al, World J. Gastroenterol. 12: 7104 (2006)), diffuse large B-cell lymphoma (DLBCL; Gascoyne, R. D. et al., Blood 102: 2568 (2003)), and non-small-cell lung cancer (NSCLC; Soda, M. et al., Nature 448: 561 (2007)).
Among ALK fusion genes identified to date, nucleophosmin (NPM) is the most common partner in ALCL (Morris, S. W. eta al., Science 263: 1281 (1994)) while echinoderm microtubule-associated protein-like-4 (EML4) is the main partner in NSCLC. NPM-ALK fusion is detected in about 75% of all ALK-positive ALCL patients and is implicated in the pathogenesis of ALCL (Li, R. et al., Med. Res. Rev. 28: 372 (2008)). EML4-ALK fusion in NSCLC was the first fusion gene found to be oncogenic in solid tumor (Mano H. et al., Cancer Sci. 99: 2349 (2008)) and was detected in approximately 5% of NSCLC patients (Koivenen, J. P. et al., Clin. Cancer Res. 14: 4275 (2008)). Moreover, genetic amplification and overexpression of ALK have been discovered to cause childhood neuroblastoma (Osajima-Hakomori, Y. et al., Am. J. Pathol. 167:213 (2005)). ALK fusion genes are oncogenic drivers in a small percentage of blood and solid tumors. ALK inhibitors are being pursued as a new class of therapy for the treatment of human cancers harboring a rearrangement of the ALK gene (ALK-positive tumors).
Crizotinib was the first ALK inhibitor approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of ALK-positive NSCLC patients. Although crizitinib is very effective in the initial stage of the treatment, acquired drug resistance caused by mutations of ALK has been identified in patients treated with crizotinib. Therefore, there is a clear need for new ALK inhibitors (second generation of ALK inhibitors), which inhibit not only wild-type ALK but also ALK mutations that are resistant to crizotinib.
Although several such second-generation ALK inhibitors, including CH5424802 (Sakamoto H, et al., Cancer Cell. 19:679 (2011)), LDK378 (Marsilje T. H, J Med Chem. 56:5675 (2013)), AP26113 (Katayama, R., Proc Natl Acad Sci USA. 108:7535 (2011)) are currently in clinical trials, it would be desirable to have additional such ALK inhibitors for the treatment of human cancers harboring ALK fusion genes.
Researchers have also discovered that a number of cancers, such as brain and lung cancers, implicate c-ros oncogene 1 (ROS1) protein. (Acquaviva J. et al., BBA-Rev. Cancer. 1795:37 (2009)). ROS1 protein is a close relative of ALK. Similar to ALK, inhibition of ROS1 provides potential treatment for diseases, such as lung and brain cancers, which are treatable by inhibition of ROS1.
The present invention provides a new class of compounds that may inhibit not only wild-type ALK but also mutated ALK and ROS1.